A microfluidic cell generally comprises one or more channels with at least one dimension equal to or less than 1 mm, more particularly in the range 100 nm to 1 mm. In use, a fluid sample is introduced into the one or more channels of the cell and analysed therein. The analysis may involve, for example, using one or more reagents disposed within the cell and arranged to react with at least a portion of the sample introduced into the cell. As such, microfluidic cells can provide integrated, portable analytical devices thereby eliminating time consuming laboratory analysis procedures.
It is also known to couple microfluidic cells with other devices such as protein arrays and mass spectrometers to further enhance analytical functionality. A review of integrated microfluidic technology is provided by D. Erickson and Dongqing Li in the review article “Integrated microfluidic devices” Analytica Chimica Acta 507 (2004) 11-26.
It has been proposed to provide an arrangement for analysing microliter amounts of a fluidic sample using nuclear magnetic resonance for NMR spectroscopy and/or NMR imaging. There are several problems associated with integrating an NMR device into a portable analytical device comprising a microfluidic cell as discussed below.
NMR devices are well known. They function on the principle that certain nuclei possess a quantum spin which generates a magnetic field. By applying a static magnetic field to a sample the spins of these nuclei are preferentially aligned with the applied magnetic field. An oscillating radiofrequency magnetic field is then applied to the sample and the frequency varied. When the oscillating magnetic field comes into resonance with a nuclear spin it flips the nuclear spin to be oriented against the direction of the static magnetic field. This transition leads to a change in the local magnetic field which can be detected. Different nuclei will spin-flip at different frequencies of the applied oscillating magnetic field due to local shielding effects of surrounding electrons and spin-spin interactions between closely spaced nuclear spins. This change in the resonance frequency of a nuclear spin due to the local chemical environment is known as NMR chemical shifting. As such, information regarding the chemical structure of the sample can be derived via an NMR spectrum indicating chemical shift data. Furthermore, if measurements are taken at numerous different positions in the sample by, for example, application of a magnetic field which varies in space, then an NMR image of the sample can be generated as in magnetic resonance imaging (MRI).
Standard NMR devices use inductive radio frequency (rf) pickup coils to both generate the oscillating magnetic field and sense changes in the magnetic field by way of NMR signals due to spin-flipping of a nuclear spin when it comes into resonance with the applied field. However, such pickup coils are very insensitive and thus relatively large sample volumes and a high magnetic field strength, typically produced by a superconducting magnet, are used to improve signal strength and increase the ability to resolve NMR chemical shifts. This results in standard NMR devices being very large and unsuitable for integration into a small, portable analytical device and/or a device which uses small sample volumes.
Alternatives to the use of inductive rf pickups coils are known for use as an NMR signal sensor. For example, magnetometers such as superconducting quantum interference devices (SQUIDs) and alkali-vapour atomic magnetometers have been suggested. However, again these devices are unsuitable for integration into small, portable analytical devices as SQUIDs require cryogenic cooling and alkali-vapour atomic magnetometers require a heated vapour cell.
WO 2009/046350 identifies the aforementioned problems with incorporating known NMR device arrangements into a microfluidic cell and suggests an alternative which uses a solid state magnetoresistive sensor. A magnetoresistive sensor comprises a thin strip of ferrous material in which a change in resistance occurs when a magnetic field is applied perpendicular to the direction of current flow. The change in resistance is measured and is indicative of changes in the localized magnetic field. In this manner, when a magnetoresistive sensor is placed in close proximity to a microfluidic channel which has been polarized by a static magnetic field, and the nuclear spins are repeatedly flipped by applying, for example, an oscillating radio frequency magnetic field, transient changes in the magnetic field strength can be detected. Such a technique can also be used for analysing electron spins, rather than nuclear spins, in an analogous manner using electron spin resonance (ESR).
One problem with the arrangement described in WO 2009/046350 is that although magnetoresistive sensors can be made small for incorporation into a microfluidic cell, they are not sufficiently sensitive to resolve precise chemical shift information without the application of a strong (>1 Tesla) homogeneous field. It is suggested that for less precise measurements more simple magnets may be used to facilitate miniaturization (see paragraph 35 of WO 2009/046350). However, it would appear from the teachings of WO 2009/046350 that a magetoresistive sensor is not sufficiently sensitive to facilitate such miniaturization when precise chemical shift information is desired due to the requirement for a strong homogeneous magnetic field to resolve such information.
It is an aim of certain embodiments of the present invention to provide an alternative arrangement to that suggested in WO 2009/046350 for integrating a spin resonance sensor into a microfluidic cell. It is a further aim to provide an arrangement which is sufficiently sensitive to resolve detailed chemical shift information at lower applied magnetic field strengths thereby facilitating miniaturization without loss of functionality.